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Biomedical subjects

G A Rook

Publications and source records attributed to G A Rook.

At least 19 recordsLinked to original sources
PubMed1995

Tuberculosis and cancer: parallels in host responses and therapeutic approaches?

Mycobacteria elicit two quite different immune responses. One is protective and is partly based on recognition and lysis of stressed, bacilli-laden cells expressing heat-shock proteins. The other suppresses this recognition and instead leads to indiscriminate necrosis of tissues containing mycobacteria (the Koch phenomenon). The type of response depends on the predominant T-cell maturation pathway, Th1 or Th2, which in turn is determined by priming by prior contact with environmental mycobacteria. Vaccination by BCG induces whichever response the recipient is primed to make, and this is a likely explanation of the variable efficacy of this vaccine in prevention of tuberculosis and therapy of cancer. Thus; BCG is a two-edged sword. We postulate that by using other mycobacterial preparations, such as killed Mycobacterium vaccae, it might be possible to suppress the indiscriminate necrosis and enhance Th1-regulated selective destruction of tumour cells.

BCG Vaccine↗
PubMed1995

Glycosylation of IgG during potentially arthritogenic lentiviral infections.

Agalactosyl IgG [Gal(0)] was first discovered in patients with rheumatoid arthritis (RA). However, the proportion of this glycoform is also raised in tuberculosis and leprosy. This has helped reinforce the suggestion that RA may be triggered by a mycobacterium-like slow bacterial infection. On the other hand, arthritis can occur in mycobacterial diseases, so raised Gal(0) could be associated with a tendency to arthritis, rather than with a particular type of infection. Therefore, we wished to find out whether the percentage of Gal(0) [%Gal(0)] is increased in sheep and goats following infection with maedi visna virus or caprine arthritis encephalitis virus (CAEV), both of which can lead to inflammatory synovitis. We found that the normal level of Gal(0) in these species is much lower than in humans. Goats infected with CAEV or Mycobacterium paratuberculosis (used as a control mycobacterial infection) had a significant increase in %Gal(0), though it was still below the level seen in normal humans. Studies by Western blot confirmed the presence of terminal N-acetylglucosamine on heavy chains, and percentages of Gal(0) comparable to those seen in human RA could be generated by exposing goat IgG to streptococcal beta-galactosidase. The rise in %Gal(0) was greatest in members of infected herds that were just starting to manifest arthritis, and tended to be lower in those in which severe carpitis had developed at the time of bleeding, implying the possibility that raise %Gal(0) may be an early or predisposing event for the development of arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosamine↗
PubMed1995

Adjuvants, endocrines and conserved epitopes; factors to consider when designing "therapeutic vaccines".

Research into immunity to complex intracellular parasites has recently placed emphasis on the identification of peptide sequences recognised by T-cells, often with the dual objectives of finding species-specific protective epitopes, and of understanding selection of Th1 versus Th2 response patterns. In this review it is suggested that although such work is interesting, it will not achieve these objectives, which must, however, be addressed before we can design the new generation of therapeutic vaccines which may eventually replace antimicrobial drugs in the treatment of infection. First, we suggest that the balance of Th1 to Th2 lymphocyte activity is not determined by epitopes, but rather by adjuvant effects of microbial components which we have barely begun to define, and local endocrine effects mediated by conversion of prohormones into active metabolites by enzymes in lymph node macrophages. Cytokines play a role as mediators within these pathways. In chronic disease states there is a tendency for T-cell function to shift towards Th2. We describe immunopathological consequences of this tendency, including a putative role for agalactosyl IgG, and review evidence for involvement of changes in the endocrine system, brought about not only by the cytokine-hypothalamus-pituitary-adrenal axis, but also by direct actions on peripheral endocrine organs of excess levels of cytokines such as TNF alpha, TGF beta and IL-6. We summarise evidence that the epitopes that are targets for protective cell-mediated responses to complex organisms are usually not species specific. In tuberculosis, cellular responses to species-specific components appear to be associated with immunopathology rather than protection. Finally, we discuss how application of these principles has led to remarkable results in the immunotherapy of tuberculosis, including multidrug-resistant disease.

Adjuvants, Immunologic↗
PubMed1995

Immunotherapy with Mycobacterium vaccae as an addition to chemotherapy for the treatment of pulmonary tuberculosis under difficult conditions in Africa.

A study to assess the impact of immunotherapy with Mycobacterium vaccae on the treatment of pulmonary tuberculosis was conducted under existing conditions in Kano, a large city in Northern Nigeria. Whilst it did not quite meet all the criteria of a well-controlled randomized or double-blind trial, the study produced results suggestive of a successful intervention. Immunotherapy with M. vaccae had a beneficial influence on clinical recovery and survival, whether given after 1, 2 or 3 weeks of chemotherapy, according to an assessment made 10-14 months after treatment. Approximately 3 weeks (19.8 days) after the onset of chemotherapy (SHRZ), 73% of the patients who received immunotherapy and 19% of those who received placebo (chemotherapy alone) had become sputum negative by microscopy for acid-fast bacilli (AFB). Similarly, a mean fall in erythrocyte sedimentation rate (ESR) of 25.4 +/- 2.50 mm and 4.0 +/- 2.29 mm was observed in the immunotherapy and placebo recipients respectively, at the same time of assessment. When weight was assessed in the two groups, it was observed that 3 weeks after starting chemotherapy, the recipients of immunotherapy had a mean weight gain of 2.90 +/- 0.24 kg whilst placebo recipients had a mean weight gain of only 0.55 +/- 0.17 kg. These parameters were re-evaluated, 10-14 months later. They showed that 11% of the recipients of the active intervention and 84.6% of placebo recipients still had demonstrable AFB in their sputum. The mean weight gain had increased to 7.91 +/- 1.03 kg and 2.04 +/- 0.94 kg in the immunotherapy and placebo recipients respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Cellular immune response to common mycobacterial antigens in subjects seropositive for Trypanosoma cruzi.

The immune response is impaired in the silent stage of Chagas' disease. We used quadruple skin-testing with new tuberculins in 37 adults who were symptom-free but seropositive for Trypanosoma cruzi and in 37 matched seronegative controls. Whereas 19% of controls responded to common mycobacterial antigens, none of the Chagas' seropositive group responded to them (p < 0.006), demonstrating specificity in their unresponsiveness. The enhanced tuberculin reactivity after BCG vaccination in the control group was suppressed in seropositive subjects (p < 0.002). Selective loss of response to common mycobacterial antigens may have implications for the autoimmune pathology of Chagas' disease, and for susceptibility to tuberculosis, leprosy, and HIV disease.

Adult↗
PubMed1994

Hormones, peripherally activated prohormones and regulation of the Th1/Th2 balance.

There is much interest in the factors that control the cytokine profile of T-helper (Th) lymphocytes, and attention has focused on feedback from the cytokines themselves. In general, Th1 cytokines promote Th1 activity and inhibit Th2 activity, and vice versa. Both Th1 and Th2 responses should therefore be stable. However, in vivo, many responses start predominantly as Th1 and then shift to Th2. Why do they do this? As discussed here, an important influence on this shift that has been largely ignored in in vitro work is the endocrine system.

Animals↗
PubMed1994

T cell helper types and endocrines in the regulation of tissue-damaging mechanisms in tuberculosis.

The necrotising immunopathology, which is accompanied by very little mycobactericidal activity, is probably the key to the pathogenesis of tuberculosis. Conventional chemotherapy fails to correct this immunoregulatory anomaly, so the host response does little to assist the drugs in the removal of the "persister" subpopulation of bacteria. Therefore chemotherapy must be prolonged for at least 6 months, with consequent problems of cost, resistance, and compliance. If we can learn to switch off the necrotising pathway, and replace it with bactericidal mechanisms, treatment of the disease will be enormously improved and shortened. One problem is that we do not know the mechanism of cell-mediated immunity to tuberculosis in man. On the other hand, we are gaining some insights into the mechanism of the necrosis, and there are encouraging indications that it can indeed be separated from immunity, and that it can be suppressed by suitable immunotherapy. We present here some evidence that when a TH2 response is superimposed upon a pre-existing TH1 response, the resulting cell-mediated inflammatory site becomes exquisitely sensitive to cytokine-mediated damage. There is clear evidence for a TH2 component in the immune response of tuberculosis patients. This inappropriate TH1 to TH2 shift may result from subtle endocrinological changes brought about by M. tuberculosis and the response to it. Immunotherapy should aim to switch off this TH2 component.

Adrenal Glands↗
PubMed1994

Identification of an antigenic domain on Mycobacterium leprae protein antigen 85B, which is specifically recognized by antibodies from patients with leprosy.

Sixty-three overlapping 15-oligomer peptides covering the 30-kDa protein antigen 85B of Mycobacterium leprae were tested by ELISA to identify epitopes recognized by human antibodies. Serum samples from patients with lepromatous leprosy (LL) reacted mainly with peptides comprising amino acid regions (AA) 206-230, 251-280, and 291-325. Sera of patients with active tuberculosis who responded to the native 30-kDa antigen did not recognize these peptides. The antibody-binding specificity to the defined B cell regions was evaluated in a blind study with 71 serum samples from patients and household contacts living in Ethiopia where leprosy is endemic. The peptide of AA 256-280 was recognized by 88% of LL patients, 15% of patients with tuberculoid leprosy, and none of the contacts. These findings suggest that there are major linear B cell epitopes on the M. leprae 30-kDa protein that are recognized by lepromin-negative LL patients, whereas lepromin-positive patients respond preferentially to conformational epitopes.

Amino Acid Sequence↗
PubMed1994

Early agalactosylation of IgG is associated with a more progressive disease course in patients with rheumatoid arthritis: results of a follow-up study.

The clinical significance of the percentage agalactosyl IgG oligosaccharides [%G(O)] was investigated in serum of a well-characterized cohort of 127 female RA patients who were followed for a mean duration of 6 yr. The %G(O) was determined in the first available serum sample which was obtained at a mean of 3.4 yr after symptom onset. It could be shown that patients with a %G(O) more than 2 S.D. above the mean level of controls (n = 34), had significantly more erosions, disease activity, and were treated with more second-line drugs, than patients without an increased %G(O) (n = 93), both at the time the serum sample was obtained, and during follow-up. These findings suggest that G(O) may serve as an indicator for the disease course in patients with RA.

Adult↗
PubMed1994

Specific detection of Mycobacterium paratuberculosis DNA associated with granulomatous tissue in Crohn's disease.

The role of mycobacteria, specifically Mycobacterium paratuberculosis, in Crohn's disease has aroused considerable controversy for many years. Using the ultra sensitive polymerase chain reaction some studies have reported detection of M paratuberculosis DNA in as many as 65% of Crohn's disease patients but also in patients without disease. Other studies have been negative for both groups. We therefore designed a double blind control trial to investigate the presence of mycobacterial DNA in age, sex, and tissue matched paraffin wax embedded tissues from 31 Crohn's disease tissues, 20 diseased gut control tissues, and 10 ulcerative colitis tissues. The specimens were coded and analysed blind with three separate polymerase chain reactions (PCR) based on DNA sequences specific for M paratuberculosis (IS900), M avium (RFLP type A/1) (IS901), and the Mycobacterium genus (65 kDa gene, TB600). The number of granulomata and presence of acid fast bacilli in each Crohn's disease tissue was also investigated. The sensitivity of the system was determined using similarly prepared gut tissue from an animal infected with M paratuberculosis. Four of 31 Crohn's disease tissues and none of the 30 control and ulcerative colitis derived tissues amplified M paratuberculosis DNA. Crohn's disease tissues containing granulomata were significantly more likely to amplify M paratuberculosis specific DNA on PCR than the non-Crohn's disease tissues (p = 0.02). All the positive Crohn's disease tissues contained granulomata, and none contained acid fast bacilli. Equivalent numbers of Crohn's and non-Crohn's disease tissues amplified the region of the 65 kD gene on PCR for non-specific mycobacterial DNA (11/31 and 9/30 respectively). No sections produced an amplified product with the IS901 PCR. These results suggest that few Crohn's disease gut biopsy sections contain M paratuberculosis DNA in association with granulomata. The absence of such DNA in any control and ulcerative colitic tissue strengthens the case for it having a specific association, which may be pathogenic, with Crohn's disease in this minority of patients.

Adult↗
PubMed1994

Galactosylation of human IgG monoclonal anti-D produced by EBV-transformed B-lymphoblastoid cell lines is dependent on culture method and affects Fc receptor-mediated functional activity.

Human monoclonal antibodies to the Rh D blood group antigen were produced by EBV-transformed B cell lines grown in serum-free medium in low density (LD) static cultures or high density (HD) hollow fiber bioreactors. Glycosylation analysis of the purified IgG was determined by the binding of anti-GlcNAc monoclonal antibody (GN7) and by analysis of oligosaccharides released by hydrazinolysis. The LD MAbs had only trace levels of agalactosyl oligosaccharides (G0), the major species (> 70%) being digalactosyl structures (G2). The HD MAbs, by contrast, contained about 10% G0 and relatively high levels (over 50%) of monogalactosyl (G1) oligosaccharides. beta 1-4 galactosyltransferase activity in the LD cell lines was similar to that found previously for other EBV-transformed B cell lines. The predominant oligosaccharides of an IgG3 anti-D, BRAD-3, contained bisecting N-acetylglucosamine. In functional assays with Fc receptor (Fc gamma R) positive effector cells, the highly galactosylated LD form of BRAD-3 was more active than the HD form in monocyte (Fc gamma RI) and K cell (Fc gamma RIII) mediated lysis of erythrocytes in ADCC assays, although these preparations showed no difference in Fc gamma RI-mediated rosette formation with U937 cells. One MAb, JAC10, was over 10-fold less active than two other IgG1 MAbs, 2B6 and BRAD-5, at mediating lysis of erythrocytes by Fc gamma RIII+ K cells; differences in sialylation may have contributed to this heterogeneity.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1994

The role of TNF-alpha in T-cell-mediated inflammation depends on the Th1/Th2 cytokine balance.

The role of tumour necrosis factor-alpha (TNF-alpha) in tuberculosis is paradoxical because although there is much evidence for a protective role, there is also evidence that it plays a part in the tissue damage that characterizes human disease. We have shown previously that TNF-alpha frequently induces necrosis when injected into sites undergoing delayed-type hypersensitivity (DTH) responses to mycobacterial antigen. This is dependent on CD4+ T cells. However the presence of this sensitivity to TNF-alpha-induced necrosis depended on the immunization protocol. We have tested the hypothesis that sensitivity to TNF-alpha depends on the cytokine profile of the induced T-cell response. All subcutaneous doses of mycobacterial immunogen used (10(7) to 10(9) organisms) primed spleen cells so that they secreted interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) when cultured in vitro with soluble antigen. However priming for production of IL-4 was dose dependent as in other systems, and was produced at all times from 7 to 30 days after immunization with 10(9) organisms. Time-course studies over 30 days showed that sensitivity to TNF-alpha was found in DTH sites of animals primed for IL-4 and IFN-gamma production, but not in animals primed only for the Th1 cytokines. We suggest therefore that the paradoxical role of TNF-alpha can be resolved. In 'pure' Th1 responses it may act as an additional macrophage-activating factor. In mixed Th1 + Th2 or Th0 responses it may cause tissue damage. This mixed pattern is characteristic of tuberculosis, and of the late stage of many chronic infections where elimination of the infecting organism is failing, and chronic tissue damage is seen.

Animals↗
PubMed1994

Selective expression of V beta families by T cells in the blood and salivary gland infiltrate of patients with primary Sjögren's syndrome.

OBJECTIVE: The T cell infiltration of the salivary gland of patients with Sjögren's syndrome (SS) has been implicated in the pathogenic process of the disease. We examined the representation of V beta subsets in the blood and salivary tissue of patients with SS. METHODS: Circulating T cells from 12 patients and paired samples of blood and labial salivary glands obtained from 8 patients were studied. A panel of monoclonal antibodies directed against the variable region of the T cell receptor was used to enumerate the cells expressing V beta families in the peripheral blood by flow cytometry, and in tissue sections by immunofluorescence. RESULTS: We found an increase of cells bearing V beta 2 family gene products in the circulation, and an increase in both V beta 2 and V beta 8 in the salivary gland infiltrate of patients with SS. No significant difference was noted between the 5 DR3+ patients and 7 DR3- patients studied with regard to the V beta families seen. CONCLUSION: Our data are consistent with a role for specific T cell families in the pathogenesis of SS.

Adult↗
PubMed1994

A longitudinal study of per cent agalactosyl IgG in tuberculosis patients receiving chemotherapy, with or without immunotherapy.

An increased percentage of circulating IgG molecules that lack galactose from the oligosaccharides on the CH2 domain correlates with disease severity in tuberculosis, rheumatoid arthritis and Crohn's disease. We have recently observed that a single injection of 10(9) autoclaved Mycobacterium vaccae given to tuberculosis patients 7 days after the initiation of chemotherapy causes accelerated clinical improvement, and clearance of bacilli from the sputum. We now show that this immunotherapy also causes rapid loss of agalactosyl IgG, detectable within 14-21 days, whereas chemotherapy alone causes agalactosyl IgG to rise further for up to 2 months. There is simultaneous inhibition of the antibody response to lipoarabinomannan, and transient enhancement of the tuberculin skin-test response. These findings are compatible with a shift from antibody production towards increased cell-mediated immunity. The ideal treatment for tuberculosis would supplement a truncated course of chemotherapy with an immunotherapeutic preparation able to down-regulate the Koch phenomenon and replace it with an efficiently bactericidal mechanism. We tentatively postulate that a fall in per cent agalactosyl IgG [%Gal(0)] in tuberculosis patients may be a marker of such a change.

Adolescent↗